Whether to treat mild hypothyroidism is controversial—but ob/gyns are increasingly concerned about links with menstrual dysfunction, infertility, early labor, and poor neurodevelopmental outcomes in offspring. In the first of two articles on subclinical thyroid disease, two experts provide the information needed to make that call.
Are you feeling increasing pressure to treat mild thyroid disease? Physicians are diagnosing such subclinical disease more and more, despite widespread disagreement and controversy about how to define and treat it. Especially in the wake of recent studies that suggest a link between both mild hypo- and hyperthyroidism and significant health risks, many of your colleagues are sensing the need to treat disease that's less than overt. In Part I, we'll focus on when you should treat mild hypothyroidism.
Coined more than 30 years ago, the term &"subclinical thyroid disease&" seems to have outlived its usefulness.1 Especially as we've better defined the clinical signs and complications of mild disease, the word subclinical has met with recurrent objections and has been replaced with &"mild.&" In stark contrast, when it comes to overt clinical disease, there's no argument about treatment or diagnosis.
In fact, mild thyroid disease is very common but still complicated by controversies over the reference values of thyroid function tests upon which we base both our diagnosis of disease and many clinical decisions. With that in mind, our goal is to not only outline treatment options and guidelines, but to discuss the definitions, causes, and factors that affect your decision to treat mild hypothyroidism.
An assay to determine thyroid-stimulating hormone (TSH) is considered the most sensitive single test for measuring thyroid status. The pituitary gland secretes TSH, where it is under the negative control of triiodothyronine (T3) derived from the circulation, or from intracellular deiodination of thyroxine (T4). TSH binds to its receptor (TSHR) on the surface of thyroid follicular cells, where it regulates the formation of and release of thyroid hormone. When there is thyroid deficiency, the serum TSH level rises; conversely, when the thyroid is overactive, the TSH level falls. Hence, when the TSH level is abnormal, serum thyroid hormone levels may provide additional information about the degree of thyroid abnormality. Keep in mind that there's considerable uncertainty about the upper limit of TSH for a normal person, while the lower limit of normal is far less controversial. That's because there are several risk factors that can confound TSH reference ranges in the general population:
As reported by most commercial assays, the upper &"normal&" limit for serum TSH is a level of ~5.0 μU/mL. These reference ranges, however, were based on control populations that included people with either occult thyroid disease or significant risk factors for thyroid disease, as stated above. Interestingly, when individuals with these risk factors were excluded from a large control group, the average TSH was ~1.5 μU/mL, with a range up to ~4.12 μU/mL.2 Furthermore, in one study, 95% of rigorously screened normal euthyroid volunteers had TSH values below 2.5 μU/mL.3
Defining mild thyroid failure. The normal ranges used in this article (Figure 1) are our conclusions from the NHANES data providing a simple upper normal range for TSH of ~4.0 μU/mL. Mild thyroid failure is defined as an increased TSH level in the presence of an apparently normal free T4 (FT4) concentration.
Prevalence. About 75% of those patients with increased TSH levels can be said to have mild hypothyroidism. The prevalence of this common condition-anywhere from 4.0% to 10.0%-is much greater in women than men.2,4 It's important to recognize patients with mild hypothyroidism since studies have now proven that some of these patients will progress to overt disease and may benefit from early treatment.
Causes of mild hypothyroidism. The causes are all similar to the causes of overt hypothyroidism, with autoimmune thyroid disease (in this case, Hashimoto's disease) the most common one. Table 1 lists known risk factors for the progression of Hashimoto's disease to overt hypothyroidism. For example, thyroid peroxidase (TPO) antibodies (which are common and indicate the presence of an intrathyroidal lymphocytic infiltrate) raise the risk of progression to overt hypothyroidism at a rate of 2% to 5% per year.5,6 Although iodine deficiency is another major cause of hypothyroidism worldwide, it's rarely seen in the United States since the introduction of iodized salt and food supplementation with iodine. Certain medications, including lithium and amiodarone, can cause iatrogenic hypothyroidism.
When diagnosing mild hypothyroidism, also be careful to exclude transient causes of hypothyroidism such as thyroiditis (including painless subacute thyroiditis and postpartum thyroiditis) and the sick euthyroid syndrome. Finally, many abnormal TSH levels arise in patients already taking T4 prepa-rations but who are unstable with their intake or have changed their preparation. Other causes of mild hypothyroidism are thyroid surgery and radioiodine.
Table 2 shows some of the clinical consequences of mild hypothyroidism, which include hyperlipidemia, cardiac dysfunction, reproductive dysfunction, and reduced quality of life.
Hyperlipidemia. The dyslipidemia of hypothyroidism is characterized by increased total cholesterol (TC) and LDL levels. TSH values in the 4.0 to 10.0 μU/mL range have been repeatedly correlated with increased TC.4,7 Furthermore, studies of patients with mild hypothyroidism have shown that thyroid treatment can lower both TC and LDL, with the greatest effect seen in those with either a TC over 240 or in those who are underreplaced with thyroxine.7,8
Cardiac dysfunction. Because thyroid hormone affects calcium uptake by the myocardium, mild thyroid disease is also associated with impaired cardiac function. For example, although the link between atrial fibrillation and hyperthyroidism is better known, patients with mild hypothyroidism also have an increased rate. At the same time, there are increases in diastolic and systolic dysfunction (especially during exercise).
One large population-based study showed that mild thyroid failure may be an independent risk factor for atherosclerosis (defined by aortic calcification) and myocardial infarction.9 While there are currently no long-term trials showing that thyroid replacement therapy reduces these cardiac risks, small studies have suggested that treatment with T4 can improve ventricular function.10,11 Another small study recently showed that thyroid hormone reduced carotid intima-media thickness, a surrogate end point for cardiovascular events.7
Mortality. Mild hypothyroidism's effect on overall mortality has been extensively studied but with unclear conclusions. Japanese re-searchers showed an increased mortality rate in men, but not in women, with mild hypothyroid-ism,12 while another population-based study of patients over age 85 actually showed mild thyroid failure to be protective (but perhaps only in patients genetically predisposed to live longer).13
Effects on reproduction. It's well known that menstrual changes, which can be seen even in mild disease, often accompany thyroid dysfunction. In fact, thyroid status affects the reproductive axis in many ways (Table 3). Hyperprolactinemia, anovulation, and possibly luteal phase deficiency caused by thyroid deficiency may contribute to reduced fertility in overt thyroid disease but have not been well documented for the mild form. On the other hand, women with thyroid antibodies are at increased risk for pregnancy loss regardless of thyroid status, with such antibodies most likely acting as a marker of immune dysfunction rather than indicating a change in thyroid status.14
Pregnancy and mild hypothyroidism. A planned pregnancy is a clear indication for treatment of even mild hypothyroidism due to the risk of poor developmental outcomes, marked in one large study by significantly lower IQ's in the offspring of hypothyroid patients.15 A recent prospective study found that roughly 2.3% of pregnancies were affected by mild thyroid disease, which was linked with an increased risk of placental abruption and preterm delivery.16 Whether these patients would benefit from T4 is debatable, underscoring the need for a large clinical trial to address this topic.
Postpartum thyroid failure. Defined as thyroid failure within the first year after childbirth, postpartum thyroid failure is more common in two groups of patients: those with pre-existing autoimmune thyroid disease (as reflected by thyroid antibodies) and patients with type 1 diabetes mellitus. This condition can present with mild hyperthyroidism followed by mild symptomatic hypothyroidism accompanied by a small goiter. It may either resolve or progress to overt hypothyroidism that can be permanent.17 Base your treatment on symptoms, and if thyroid replacement is started, monitor a patient closely, as many patients resolve.
Patients with mild hypothyroidism have more symptoms than patients with a normal thyroid (Table 4).18
For now, it's not possible to give an evidence-based conclusion that treatment improves the symptoms of mild hypothyroidism. Various symptoms, however, can be important in reaching a decision to treat when guided by the overall clinical picture that emerges. As the first step in deciding whether to treat a patient, confirm your diagnosis by repeating the TSH testing. At that time, you should obtain thyroid peroxidase and thyroglobulin antibodies and a fasting lipid panel. The decision to treat then depends on both the clinical picture and the level of TSH elevation (Figure 1).
The current area of controversy is whether to treat the patient with a TSH level between 4.0 and 10.0 μU/mL. For a normal, healthy woman we have defined the upper limit of normal TSH as 4.0 μU/mL. However, for an older patient with a history of cardiac disease, consider the upper limit of normal to be much higher. Often 10.0 μU/mL is taken as the level above which to start treatment because of the increased risks associated with thyroxine therapy in these patients. Currently, there's no evidence in favor of treating the group of patients in the 2.5 to 4.0 μU/mL range although such TSH levels are likely markers of thyroid dysfunction in the presence of thyroid autoantibodies.
Symptoms and risk factors. If any of the following symptoms or risk factors for progression are present, treatment should be strongly considered. In the setting of an elevated TSH, we would consider any of these as reasons to start therapy:
Factors against treatment. As discussed earlier, these include increasing age or a history of arrhythmias, or known ischemic heart disease. Take into consideration that during the course of T4 treatment, up to 20% of patients are not correctly titrated for a normal TSH level.19 Therefore, treatment itself carries risk, especially in the elderly or those with known arrhythmias.
Goals of treatment. Your goal for most patients that you treat should be to normalize TSH to ~1.0 μU/mL. An argument can still be made to withhold treatment in women with serum TSH levels of 4.0 to 10.0.20 However, in our view, in the presence of two or more risk factors, as defined above, withholding treatment is not justified.
What to treat with. Treatment must be carefully tailored to the individual, especially those with symptoms. Only pure T4 should be used to treat hypothyroidism. Don't use T3 by itself because it is rapidly absorbed and has a short half-life, which can lead to variable levels throughout the day and palpitations and arrhythmias at its peak. Nor should you use desiccated thyroid (which contains both T3 and T4) due to wide variability in the T3 concentrations seen in commercial preparations, which can lead to an unphysiologic ratio of T4 and T3. Instruct a patient to take her thyroxine tablets alone 1 hour before eating and at least 4 hours apart from all other pills, because many medicines and supplements can interfere with absorption (including calcium and iron supplements and multivitamins).
Thyroxine dosing. In a young, healthy patient with mild thyroid failure, a starting thyroxine dose of 50 or 75 μg/kg/day may be all that's needed depending upon her weight (a full replacement dose is 1.6 μg/kg/day). Give older patients 25 μg/kg/day and monitor them carefully before increasing towards the dose sufficient to bring the TSH level nearer the normal range. As discussed below, pregnant patients or those taking estrogen or an oral contraceptive may require more thyroxine than expected. The goal for most patients should be a TSH of about 1.0 μU/mL, which will usually lead to free T4 levels in the upper third of the normal reference range. Given the 1-week plasma half-life of T4, it takes about 6 weeks to reach a steady state after treatment is begun or after a dose is changed. TSH levels should, therefore, be repeated only after 6 weeks and adjusted until the TSH goal is met. If you're only observing and not treating a patient, repeat thyroid function tests at 6- to 12-month intervals.
Thyroid hormone replacement in pregnancy. Factors that raise thyroid hormone metabolism include increases in the following: weight and circulatory volume, thyroxine binding globulin (TBG), glomerular filtration rate leading to enhanced iodine loss from the kidney, and in the metabolism of T4 by the placenta. To predict T4 doses in pregnancy: (1) Assess TSH and free T4 levels every 4 to 6 weeks and (2) Understand that TSH is low during the first trimester in normal pregnancy due to the fact that hCG mildly stimulates thyroid hormone output. (On average, more than 50% of patients will need their T4 increased by up to 50%.)
Generic or brand name thyroxine? Many thyroid preparations are now on the market for thyroid hormone replacement, including four brands of synthetic T4. Be aware that these commercial brands of T4 are not bioequivalent and have been the subject of much discussion by and with the FDA (see the American Thyroid Association Web site: http://www.thyroid.org/.) This is important because of the narrow therapeutic range for T4, as evidenced by the need for multiple tablet doses. Switching between different manufacturers preparations should therefore be avoided. The same discussion applies to generic T4 preparations since it's not possible to know which generic a patient is receiving and there's unlikely to be any continuity on refilling a prescription.
Mild thyroid disease is being increasingly diagnosed. Large epidemiologic studies show that there is a fairly narrow range of normal TSH, which should guide diagnosis and treatment. Mild hypothyroid-ism is common, and is associated with dyslipidemia, cardiac dysfunction, and increased mortality rates. In reproductive-aged women, mild hypothyroidism is associated with menstrual dysfunction, infertility, and possibly early labor and poor neurodevelopmental outcomes in the offspring of these patients. In our opinion, mild hypothyroidism (especially in the presence of symptoms or risk factors for progression) should be treated with T4 to a goal TSH of ~1.0 μU/mL unless contraindicated.
1. Evered DC, Ormston BJ, Smith PA, et al. Grades of hypothyroidism. Br Med J. 1973;1(5854):657-662.
2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499.
3. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13:3-126.
4. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526-534.
5. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55-68.
6. Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87:3221-3226.
7. Monzani F, Caraccio N, Kozakowa M, et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004;89:2099-2106.
8. Danese MD, Ladenson PW, Meinert CL, et al. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85:2993-3001.
9. Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132:270-278.
10. Faber J, Petersen L, Wiinberg N, et al. Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid. 2002;12:319-324.
11. Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001;86:1110-1115.
12. Imaizumi M, Akahoshi M, Ichimaru S, et al. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004;89:3365-3370.
13. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292:2591-2599.
14. Poppe K, Velkeniers B. Female infertility and the thyroid. Best Pract Res Clin Endocrinol Metab. 2004;18:153-165.
15. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341:549-555.
16. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol. 2005;105:239-245.
17. Premawardhana LD, Parkes AB, Ammari F, et al. Postpartum thyroiditis and long-term thyroid status: prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab. 2000;85:71-75.
18. Cooper DS, Halpern R, Wood LC, et al. L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med. 1984;101:18-24.
19. Parle JV, Franklyn JA, Cross KW, et al. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract. 1993;43:107-109.
20. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;14;291:228-238.
To earn CME credit for this activity, participants should read the article and log onto http://www.contemporaryobgyn.net/ where they must pass a post-test. After completing the test and online evaluation, a CME certificate will be e-mailed to them. The release date for this activity is January 1, 2006. The expiration date is January 1, 2007.
Upon completion of this article, participants will be able to:
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Thomson American Health Consultants (AHC) and Contemporary OB/GYN. Thomson American Health Consultants is accredited by the ACCME to provide continuing medical education for physicians.
AHC designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.
Obstetrician/gynecologists and women's health practitioners.
The authors of this article (Rebecca Fenichel, MD, and Terry F. Davies, MD) report the following relationships with companies having ties to this field of study: Dr. Fenichel reports no relationship with companies having ties to this field of study. Dr. Davies reports that he is on the Speakers Bureau for Abbott Pharmaceuticals (which makes the drug levothyroxine sodium) and on the Board of Kronus Corp., Boise, Idaho (which makes diagnostic kits for thyroid antibodies.) Editors Judith M. Orvos and Elizabeth A. Nissen disclose that they do not have any financial relationships with any manufacturer in this therapeutic category.